| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Alpha-1 Antitrypsin Deficiency related liver disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Alpha-1 Antitrypsin Deficiency related liver disease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001806 |
| E.1.2 | Term | Alpha-1 anti-trypsin deficiency |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the safety and tolerability of multiple doses of ARC-AAT Injection |
|
| E.2.2 | Secondary objectives of the trial |
| To determine the effect of multiple doses of ARC-AAT Injection on circulating levels of alpha-1 antitrypsin |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for enrollment, participants must meet all of the following inclusion criteria:
1. Male or non-nursing female patients 18-75 years of age, inclusive, at the time of Screening with previous diagnosis of PiZZ genotype Alpha-1 Antitrypsin Deficiency. Availability of documented PiZ phenotype is sufficient to allow enrollment but a confirmatory genotype must be performed.
2. Able and willing to provide written informed consent prior to the performance of any study specific procedures.
3. Participants with a BMI between 18.0 and 35.0 kg/m2, inclusive. Participants with BMI between 15-18 kg/m2 or between 35-40 kg/m2 may be enrolled at the PI’s discretion in consultation with Sponsor depending on co-morbidities.
4. A 12-lead ECG at Screening that, in the opinion of the investigator, has no abnormalities that compromise participant’s safety in this study.
5. Non-smoker (not a daily cigarette smoker) for at least 12 months with current non-smoking status confirmed by urine cotinine at screening. Patients may be on nicotine replacement (patch or gum).e-cigarettes (vapor) is not permitted. A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the PI.
6. Participants using highly effective, double barrier contraception (both male and female partners) during the study and for 3 months following the last dose of ARC-AAT Injection. Males must not donate sperm for at least 3 months post last dose of study treatment. Male partners of female patients and female partners of male patients must also use contraception, if they are of childbearing potential. Females of childbearing potential must have a negative urine pregnancy test at Screening and on Day 1 pre-dose. Females not of childbearing potential must be postmenopausal (defined as cessation of regular menstrual periods for at least 12 months), confirmed by follicle-stimulating hormone (FSH) level > 40 mIU/mL or as otherwise consistent with postmenopausal state based on lab reference ranges.
• Using twice the normal protection of birth control by using a condom AND one other form from the following:
• Birth control pills (The Pill)
• Depot or injectable birth control
• IUD (Intrauterine Device)
• Birth Control Patch (e.g., Othro Evra)
• NuvaRing®
• Surgical sterilization. i.e., tubal ligation, hysterectomy, bilateral oophorectomy, vasectomy or equivalently effective surgical form of birth control. Rhythm methods will not be considered as highly effective methods of birth control.
7. Participants who are willing and able to comply with all study assessments and adhere to the protocol schedule
8. Must have suitable venous access for blood sampling
9. No abnormal finding of clinical relevance at the Screening evaluation that in the opinion of the investigator could adversely impact subject safety during the study or adversely impact study results.
10. ALT, AST levels less than 5X times the upper limit of normal at Screening
11. Creatinine levels < 1.5X upper limit of normal and estimated (calculated) GFR > or equal to 60 at Screening
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| E.4 | Principal exclusion criteria |
A potential participant will be excluded from the study if any of the following criteria apply:
1. INR > 1.3. If based on opinion of PI and/or prescribing physician patient is appropriate for anticoagulant holiday, patient may stop taking anticoagulant for an appropriate washout period and if indicated a repeat INR within < 1.3 would be acceptable. If INR is not indicated (direct thrombin inhibitors or Xa inhibitors) then appropriate washout period alone may be acceptable.
(Note: Anti-platelet agents aspirin, clopidogrel or NSAIDS are acceptable but must be held 7 days before and 7 days after liver biopsy)
2. Platelet count < 70,000
3. A known diagnosis of hepatic fibrosis from a cause other than AATD (such as non-alcoholic steatohepatitis, alcoholism or infection)
4. A history of poorly controlled autoimmune disease, or any history of autoimmune hepatitis
5. Human immunodeficiency virus infection, as shown by the presence of anti-HIV antibody (seropositive)
6. Seropositive for HBV or HCV
7. Uncontrolled hypertension (Systolic BP > 170 and diastolic BP >100 mmHg at Screening)
8. A history of torsades de pointes, ventricular rhythm disturbances (e.g., ventricular tachycardia or fibrillation), pathologic sinus bradycardia (<50 bpm and symptomatic), heart block (excluding first-degree block, being PR interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG. Participants with a history of atrial arrhythmias should be discussed with the Medical Monitor
9. A family history of congenital long QT syndrome or unexplained sudden cardiac death
10. Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction < 20%, transient ischemic attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to study entry
11. History of malignancy within the last 2 years except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with other curatively treated malignancies who have no evidence of metastatic disease and >1 year disease-free interval may be entered following approval by the Medical Monitor
12. History of major surgery within 1 month of Screening
13. Regular use of alcohol within one month prior to the Screening visit (i.e., more than fourteen units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol])
14. Use of illicit drugs (such as cocaine, phencyclidine [PCP] and crack) within 1 year prior to the
Screening visit or positive urine drug screen at Screening (a urine drug screen positive for benzodiazepines, opioids or marijuana is acceptable for enrollment at the discretion of the PI)
15. History of known allergy to bee venom, any history of anaphylaxis or any history of severe systemic hypersensitivity reaction
16. Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving a therapeutic intervention. Subjects who have participated in the ARCAAT-1001 study or observational studies are acceptable.
17. Any clinically significant history or presence of poorly controlled or decompensated neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, metabolic or other uncontrolled systemic disease.
18. Blood donation (≥500 mL) within 7 days prior to study treatment administration.
19. Any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or put the participant at additional safety risk
20. A history of thromboembolic disease (including deep vein thrombosis or pulmonary embolism), myocardial infarction, stroke within six (6) months of screening.
21. Participants who are unable to return for all scheduled study visits
22. Any other condition, that in the opinion of the investigator would render the participant unsuitable for enrollment, or could interfere with participating in and completing the study
23. FEV1 at baseline < 50% (this criterion is only applicable if not on AAT augmentation therapy.
For subjects on augmentation therapy FEV1 < 30% will be exclusionary). Pertinent study FEV1 will be based on post-bronchodilation value.
24. AATD Patients with liver Elastography (i.e. FibroScan®) score > 12.5 at Screening
25. Planned surgery requiring an induction agent (e.g. ketamine, etomidate) within 48 hours (both before and after) of IP administration.
Note: Sponsor medical monitor has the option to exclude the enrollment of a participant if, based upon the participant’s medical history or Screening results, it is felt that a participant’s safety may be at risk.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and tolerability of repeated doses of ARC-AAT Injection.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| See Schedule of Assessments |
|
| E.5.2 | Secondary end point(s) |
| Serum alpha-1 antitrypsin levels |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Pre-dose; Dosing Days 1, 29, 57, 85, 113, 141, 169; Days 197, 227, 257, 287 (EOS) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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